Influence of memantine on nociceptive responses of the trigeminocervical complex after formalin injection

Background: Glutamate receptors are implicated in central nervous system (CNS) pain pathways, including trigeminovascular activation, central sensitization, and cortical spreading depression. Methods: We investigated the influence of the N-methyl-d-aspartate (NMDA) receptor antagonist memantine on pain pathways involving trigeminocervical complex (TCC) using a formalin injection model. In Sprague Dawley rats, formalin was delivered into the left periorbital area. Memantine (10 mg/kg) or vehicle was injected intraperitoneally 30 min before the formalin injection. The sensory threshold for mechanical stimulation, assessed by the von Frey monofilament threshold (VFMF), was measured 1 h and 2 h after formalin injection. Formalin-induced pain behavior was measured by monitoring the time spent rubbing the injected area during 60 min after formalin injection. The brainstem was then removed, and sections that spanned the TCC were cut, and stained with a Fos antibody. Results: Pretreatment with memantine significantly attenuated formalin-induced pain behavior (p < 0.01) and the sensory threshold for VFMF (p < 0.001). In the TCC, the increase in formalin-induced Fos immunoreactivity was significantly attenuated in the memantine group (p < 0.01). Conclusion: The present study demonstrated that the NMDA receptor antagonist memantine inhibits the nociceptive process from trigemino-ophthalmic nerve endings to the TCC.